The applicant is a clinical genetics fellow with previous broad clinical experience. The goal of this proposal is for him to become an independent clinical investigator in the genetic dissection of complex diseases, through graduate level courses and mentored research. Specific courses will include molecular genetics, genetic epidemiology, research study design, and ethical conduct of scientific research. The research setting will be the Baylor College of Medicine, a center of excellence in genetic research. Facilities include a genotyping center and a sequencing center affiliated with the Human Genome Project. Mentored research will be performed on the genetics of the left ventricular outflow tract obstruction (LVOTO) subgroup of congenital cardiovascular malformations (CCVM). This group accounts for ~20% of all CCVM and are important contributors to overall neonatal mortality. Various lines of embryological, epidemiological, and cytogenetic evidence point to the importance of genetic factors, but most cases are sporadic, indicating the genetic components are complex and do not conform to a simple pattern of inheritance. The first Specific Aim is to investigate LVOTO genetics by the linkage approach on multiplex LVOTO families and affected sib pairs. The second Specific Aim is to study family members of affected cases by echocardiography, to search for quantitative measurements that might be useful for mapping quantitative trait loci contributing to left heart development. The third Specific Aim is to establish and test affected-child/parent trios in association studies by transmission dysequilibrium and likelihood ratio analyses. Approximately 50 candidate genes, suggested primarily by mouse knockout phenotypes, will be examined in over 300 samples. The fourth Specific Aim will be to screen for mutations in candidate genes identified through animal models in the literature or identified by our linkage and association studies above. The proposed studies will launch the applicant on an independent research career, providing a base on which to advance genetic analyses of CCVM with the aim to reduce their occurrence and provide new treatment opportunities.
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